Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatitis C virus (HCV) coinfection is implicated in many of these cases, but other causes of liver injury are common in HIV infection. Elucidation of the factors responsible for liver disease among HIV-infected patients, with or without concurrent HCV is important for researchers who seek to understand the pathogenesis of liver disease, and for clinicians who treat this large group of patients. Hepatic steatosis (or fatty liver) is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in those with HIV/HCV coinfection. However, relatively little is known about the etiology of steatosis in HIV infection. In HCV infection, genotype 3 appears to be directly associated with steatosis, but is uncommon in the US. By contrast, in those with genotype 1 HCV infection (which is highly prevalent in the US), obesity may be a more important cause than HCV infection. In the absence of HCV infection, obesity is a common cause of steatosis;however, visceral obesity (which is the accumulation of adipose tissue around the viscera) may be a more important risk factor than overall body mass for steatosis. Different studies suggest that the consequences of visceral obesity (increased inflammatory cytokines, decreased adiponectin, insulin resistance, increased circulating free fatty acids or microbial translocation of gut-derived endotoxins) may induce steatosis. These potential mediators could also explain the proposed link between HIV infection (independent of visceral obesity) and steatosis. HIV replication has been associated with elevations in inflammatory markers;HIV- associated peripheral lipoatrophy with decreased adiponectin levels. HIV infection has also been associated with depletion of gut-associated lymphoid tissue leading to a """"""""leaky gut"""""""" and microbial translocation. Thus there is reason to believe that HIV infection will be an important risk factor for steatosis, independent of HCV and visceral adiposity. We propose the following hypotheses: (1.1) HIV infection (alone or in combination with HCV) will be associated with a greater severity of steatosis than in those with neither infection;(1.2) Increased visceral adiposity will be associated with severity of steatosis;(1.3) Peripheral lipoatrophy and gut-associated microbial translocation will be the dominant factors associated with steatosis in HIV-infected patients;(2.1) After controlling for HIV, HCV, and visceral adiposity, insulin resistance will remain strongly associated with the severity of steatosis;(2.2) Circulating free fatty acid levels will be a dominant predictor of steatosis due to the increased free fatty acid flux to the liver from increased visceral adiposity and the inability to store fatty acids in the setting of HIV-associated subcutaneous adipose tissue loss;(2.3) Decreased adiponectin levels (due to HIV-associated lipoatrophy and inflammation) will explain a significant proportion of the HIV effect on steatosis;(3.1) HIV/HCV-coinfected will have a greater prevalence and degree of histologic steatohepatitis and fibrosis than HCV-monoinfected patients, due to an increased severity of steatosis;(3.2) Increased inflammation, decreased adiponectin, increased free fatty acids, and insulin resistance will explain the greater prevalence and degree of histologic steatohepatitis and fibrosis in HIV/HCV-coinfected compared to HCV- monoinfected patients. The objective of the proposed study is to identify the dominant biologic mediators of steatosis, in order to focus future mechanistic and interventional studies on the key pathways associated with the pathogenesis of steatosis and its progression. To accomplish this, 300 men and 100 women with HIV and HCV monoinfection, HIV/HCV coinfection and neither infection will be studied. State-of-the-art non-invasive magnetic resonance spectroscopy (MRS) will measure steatosis. MRS studies a larger area than a random core biopsy of liver tissue, provides a continuous measure of liver fat, and allows for the study of patients with HIV monoinfection and neither infection;biopsy is not clinically indicated in those without chronic liver disease.

Public Health Relevance

Public Health Relevance: Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatic steatosis (or fatty liver) is a frequent cause of liver disease in the US and is a particular concern for HIV-infected persons. Steatosis is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in HIV/HCV-coinfected persons. HCV infection appears directly associated with steatosis, but the etiology of steatosis in HIV remains unclear. Obesity (in particular, visceral obesity) appears to be a key promoter of steatosis in the absence of viral infection. Studies show that about 50% of HIV-infected and 75% of HIV-uninfected persons in the US are overweight or obese. It is therefore critical to understand the relation of HIV, HCV, and visceral adiposity with steatosis, and to identify biologic mediators (microbial translocation, inflammation, adipokine and metabolic alterations) in the pathogenesis of steatosis, so that interventions targeted to the dominant factors can be developed and studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087176-02
Application #
8094315
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Brobst, Susan W
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$540,263
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Kardashian, Ani; Ma, Yifei; Scherzer, Rebecca et al. (2017) Sex differences in the association of HIV infection with hepatic steatosis. AIDS 31:365-373
Price, Jennifer C; Dodge, Jennifer L; Ma, Yifei et al. (2017) Controlled attenuation parameter and magnetic resonance spectroscopy-measured liver steatosis are discordant in obese HIV-infected adults. AIDS 31:2119-2125
Reid, Michael; Ma, Yifei; Scherzer, Rebecca et al. (2017) Higher CD163 levels are associated with insulin resistance in hepatitis C virus-infected and HIV-infected adults. AIDS 31:385-393
Price, Jennifer C; Ma, Yifei; Scherzer, Rebecca et al. (2017) Human immunodeficiency virus-infected and uninfected adults with non-genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection. Hepatology 65:853-863
Swanson, Sophia; Ma, Yifei; Scherzer, Rebecca et al. (2016) Association of HIV, Hepatitis C Virus, and Liver Fibrosis Severity With the Enhanced Liver Fibrosis Score. J Infect Dis 213:1079-86
Kelly, Erin M; Dodge, Jennifer L; Sarkar, Monika et al. (2016) Marijuana Use Is Not Associated With Progression to Advanced Liver Fibrosis in HIV/Hepatitis C Virus-coinfected Women. Clin Infect Dis 63:512-8
Sharma, Anjali; Ma, Yifei; Scherzer, Rebecca et al. (2016) Brief Report: Association of Adipokines With Bone Mineral Density in HIV-Infected and HIV-Uninfected Women. J Acquir Immune Defic Syndr 73:433-437
Peters, Marion G; Bacchetti, Peter; Boylan, Ross et al. (2016) Enhanced liver fibrosis marker as a noninvasive predictor of mortality in HIV/hepatitis C virus-coinfected women from a multicenter study of women with or at risk for HIV. AIDS 30:723-9
Tien, Phyllis C (2015) Novel Approaches to Targeting Visceral and Hepatic Adiposities in HIV-Associated Lipodystrophy. Curr Atheroscler Rep 17:73
Shah, Shailja; Ma, Yifei; Scherzer, Rebecca et al. (2015) Association of HIV, hepatitis C virus and liver fibrosis severity with interleukin-6 and C-reactive protein levels. AIDS 29:1325-33

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